In previous studies, we demonstrated that HLA class I and class II molecules (specifically HLA-DR) were preferentially incorporated in the human immunodeficiency virus-1 (HIV-1) or simian immunodeficiency virus (SIV-1) virions when virus was grown in cells expressing these molecules. Monkeys immunized with purified HLA class I and class II molecules developed antibodies to these molecules; however, only those monkeys with antibodies to HLA-DR were protected from subsequent challenge with SIV grown in human cells. Regions of sequence homology between HIV small envelope (gp41) and large envelope (gp120) proteins and class I and II molecules have been identified by ourselves and others. Sera from the protected monkeys were tested for reactivity to selected gp41 and gp120 HIV-1 and SIV-1 peptides. Reactivity was observed with sera containing class II antibodies to HIV-1 peptides only. In another study, sera from mothers transmitting virus to offspring had an increased frequency of reactivity to peptides in a region of gp41 that has been demonstrated by others to be the site of reactivity of human enhancing antibodies. The HLA-class II molecules (HLA-DR) present antigen to responding T-cells. In the normal immune response, other adhesion molecules on the antigen- presenting cell that are not present on the virion are necessary in order for the T-cell to respond. In the absence of adhesion molecules, the responding T-cells undergo programmed cell death or apoptosis. T-cells responding to tetanus toxoid were expanded in vitro and exposed to concentrated virions grown in macrophages that had been pulsed with tetanus toxoid. After exposure, the T-cells were tested for virus infection by p24 assays and apoptosis using flow cytometric techniques. T-cells exposed to the virions obtained from the monocyte/macrophages pulsed with tetanus toxoid underwent apoptosis with little to no infection detected. In contrast, virions obtained from macrophages that had not been pulsed with tetanus toxoid did not induce apoptosis in the responding cell population. These results indicate that the HIV-1 virion can induce T-cell death in the absence of infection.